EU-LIFE charter of independent life science research institutes.

The diverse range of organizations contributing to the global research ecosystem is believed to enhance the overall quality and resilience of its output. Mid-sized autonomous research institutes, distinct from universities, play a crucial role in this landscape. They often lead the way in new research fields and experimental methods, including those in social and organizational domains, which are vital for driving innovation. The EU-LIFE alliance was established with the goal of fostering excellence by developing and disseminating best practices among European biomedical research institutes. As directors of the 15 EU-LIFE institutes, we have spent a decade comparing and refining our processes. Now, we are eager to share the insights we've gained. To this end, we have crafted this Charter, outlining 10 principles we deem essential for research institutes to flourish and achieve ground-breaking discoveries. These principles, detailed in the Charter, encompass excellence, independence, training, internationality and inclusivity, mission focus, technological advancement, administrative innovation, cooperation, societal impact, and public engagement. Our aim is to inspire the establishment of new institutes that adhere to these principles and to raise awareness about their significance. We are convinced that they should be viewed a crucial component of any national and international innovation strategies.

Ceftriaxone-Induced Encephalopathy in a Patient With Chronic Kidney Disease.

Neurotoxicity is an acknowledged side effect of third and fourth-generation cephalosporins, but its occurrence with ceftriaxone is not widely recognized. This article presents a case involving a 56-year-old woman with multiple comorbidities who sought medical attention after experiencing lipothymia. The initial diagnosis suggested a urinary tract infection with acute kidney failure, leading to the initiation of ceftriaxone and hemodialysis. Subsequently, the patient exhibited a progressive deterioration of her neurological state, characterized by agitation and chorea. Metabolic encephalopathy, seizure/nonconvulsive status epilepticus, and acute central nervous system lesions were considered primary differential diagnoses, all of which were subsequently ruled out through thorough investigations. Days later, a remarkable recovery of the patient's neurological state was observed. A retrospective analysis revealed a correlation between the improvement and the fourth day of antimicrobial suspension. Consequently, a presumptive diagnosis of ceftriaxone-induced encephalopathy was made. This unusual case underscores the importance of recognizing the potential for pharmacological encephalopathy, particularly with ceftriaxone, and emphasizes its reversibility upon discontinuation of the implicated drug. Clinicians should remain vigilant to this uncommon adverse effect, promoting timely intervention and improved patient outcomes.

IFT88 maintains sensory function by localising signalling proteins along Drosophila cilia.

Ciliary defects cause several ciliopathies, some of which have late onset, suggesting cilia are actively maintained. Still, we have a poor understanding of the mechanisms underlying their maintenance. Here, we show Drosophila melanogaster IFT88 (DmIFT88/nompB) continues to move along fully formed sensory cilia. We further identify Inactive, a TRPV channel subunit involved in Drosophila hearing and negative-gravitaxis behaviour, and a yet uncharacterised Drosophila Guanylyl Cyclase 2d (DmGucy2d/CG34357) as DmIFT88 cargoes. We also show DmIFT88 binding to the cyclase´s intracellular part, which is evolutionarily conserved and mutated in several degenerative retinal diseases, is important for the ciliary localisation of DmGucy2d. Finally, acute knockdown of both DmIFT88 and DmGucy2d in ciliated neurons of adult flies caused defects in the maintenance of cilium function, impairing hearing and negative-gravitaxis behaviour, but did not significantly affect ciliary ultrastructure. We conclude that the sensory ciliary function underlying hearing in the adult fly requires an active maintenance program which involves DmIFT88 and at least two of its signalling transmembrane cargoes, DmGucy2d and Inactive.

Ana1/CEP295 is an essential player in the centrosome maintenance program regulated by Polo kinase and the PCM.

Centrioles are part of centrosomes and cilia, which are microtubule organising centres (MTOC) with diverse functions. Despite their stability, centrioles can disappear during differentiation, such as in oocytes, but little is known about the regulation of their structural integrity. Our previous research revealed that the pericentriolar material (PCM) that surrounds centrioles and its recruiter, Polo kinase, are downregulated in oogenesis and sufficient for maintaining both centrosome structural integrity and MTOC activity. We now show that the expression of specific components of the centriole cartwheel and wall, including ANA1/CEP295, is essential for maintaining centrosome integrity. We find that Polo kinase requires ANA1 to promote centriole stability in cultured cells and eggs. In addition, ANA1 expression prevents the loss of centrioles observed upon PCM-downregulation. However, the centrioles maintained by overexpressing and tethering ANA1 are inactive, unlike the MTOCs observed upon tethering Polo kinase. These findings demonstrate that several centriole components are needed to maintain centrosome structure. Our study also highlights that centrioles are more dynamic than previously believed, with their structural stability relying on the continuous expression of multiple components.

Novel Characterization Techniques for Multifunctional Plasmonic-Magnetic Nanoparticles in Biomedical Applications.

In the rapidly emerging field of biomedical applications, multifunctional nanoparticles, especially those containing magnetic and plasmonic components, have gained significant attention due to their combined properties. These hybrid systems, often composed of iron oxide and gold, provide both magnetic and optical functionalities and offer promising avenues for applications in multimodal bioimaging, hyperthermal therapies, and magnetically driven selective delivery. This paper focuses on the implementation of advanced characterization methods, comparing statistical analyses of individual multifunctional particle properties with macroscopic properties as a way of fine-tuning synthetic methodologies for their fabrication methods. Special emphasis is placed on the size-dependent properties, biocompatibility, and challenges that can arise from this versatile nanometric system. In order to ensure the quality and applicability of these particles, various novel methods for characterizing the magnetic gold particles, including the analysis of their morphology, optical response, and magnetic response, are also discussed, with the overall goal of optimizing the fabrication of this complex system and thus enhancing its potential as a preferred diagnostic agent.

The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years.

OBJECTIVE: To verify from a systematic literature review the possible effects of thyroid diseases on assisted reproduction techniques. DATA SOURCES: The studies were analyzed from the PubMed, Cochrane Library, LILACS databases. SELECTION OF STUDIES: The articles selected for the review included: cross-sectional studies, cohort studies, and clinical trials that addressed the proposed theme and which were published within the period stipulated from January 1, 2012, to March 5, 2022, in English, Portuguese and Spanish. These would later have to go through stages of inclusion as a framework of the type of study and exclusion criteria that were review articles, case reports, abstracts, articles with animal models, and duplicate articles and letters to the editor. DATA COLLECTION: Author's name; Number of patients; Clinical outcome; Use of drugs; Control group (in case it had); Clinical outcome. DATA SYNTHESIS: In in vitro fertilization and intracytoplasmic sperm injection it was verified that thyroid diseases can lead to effects such as a reduction in the rate of recovered oocytes, a decrease in the number of embryos, lower pregnancy rates, and increased chances of congenital anomalies in these patients and a reduction in the rate of implantation. Levothyroxine can increase the number of cycle cancellations. CONCLUSIONS: Thyroid diseases may have deleterious effects on the clinical outcome of in vitro fertilization and intracytoplasmic sperm injection.

Exploring the reasons for labour market gender inequality a year into the COVID-19 pandemic: evidence from the UK cohort studies.

The COVID-19 pandemic has caused unexpected disruptions to Western countries which affected women more adversely than men. Previous studies suggest that gender differences are attributable to: women being over-represented in the most affected sectors of the economy, women's labour market disadvantage as compared to their partners, and mothers taking a bigger share childcare responsibilities following school closures. Using the data from four British nationally representative cohort studies, we test these propositions. Our findings confirm that the adverse labour market effects were still experienced by women a year into the COVID-19 pandemic and that these effects were the most severe for women who lived with a partner and children, even if they worked in critical occupations. We show that adjusting for pre-pandemic job characteristics attenuates the gaps, suggesting that women were over-represented in jobs disproportionately affected by COVID-19 pandemic. However, the remaining gaps are not further attenuated by adjusting for the partner's job and children characteristics, suggesting that the adversities experienced by women were not driven by their relative labour market position, as compared to their partners or childcare responsibilities. The residual gender differences observed in the rates of active, paid work and furlough for those who live with partner and children point to the importance of unobserved factors such as social norms, preferences, or discrimination. These effects may be long-lasting and jeopardise women's longer-term position through the loss of experience, leading to reinforcement of gender inequalities or even reversal of the progress towards gender equality.

Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype.

Polo-like kinase 4 (Plk4), the major regulator of centriole biogenesis, has emerged as a putative therapeutic target in cancer due to its abnormal expression in human carcinomas, leading to centrosome number deregulation, mitotic defects and chromosomal instability. Moreover, Plk4 deregulation promotes tumor growth and metastasis in mouse models and is significantly associated with poor patient prognosis. Here, we further investigate the role of Plk4 in carcinogenesis and show that its overexpression significantly potentiates resistance to cell death by anoikis of nontumorigenic p53 knock-out (p53KO) mammary epithelial cells. Importantly, this effect is independent of Plk4's role in centrosome biogenesis, suggesting that this kinase has additional cellular functions. Interestingly, the Plk4-induced anoikis resistance is associated with the induction of a stable hybrid epithelial-mesenchymal phenotype and is partially dependent on P-cadherin upregulation. Furthermore, we found that the conditioned media of Plk4-induced p53KO mammary epithelial cells also induces anoikis resistance of breast cancer cells in a paracrine way, being also partially dependent on soluble P-cadherin secretion. Our work shows, for the first time, that high expression levels of Plk4 induce anoikis resistance of both mammary epithelial cells with p53KO background, as well as of breast cancer cells exposed to their secretome, which is partially mediated through P-cadherin upregulation. These results reinforce the idea that Plk4, independently of its role in centrosome biogenesis, functions as an oncogene, by impacting the tumor microenvironment to promote malignancy.

Parent Training Procedures in Mental Health Field: A Systematic Literature Review / Procedimentos de Treino de Pais no Âmbito da Saúde Mental: Uma Revisão Sistemática da Literatura

ABSTRACT We sought to answer which procedures have been used to train parents within the mental health field, how often the behavior skills training (BST), as well as its components, is used, and how effective such procedures are. In order to do so, a systematic literature review, using the Education Collection ProQuest database, was conducted. The search terms used were "behavior skills training", "parents", and its correlates in Portuguese. Papers published between 2010 and 2019 were analyzed, focusing on parent training procedures and their effects. Among the 28 analyzed papers, 4 of them used BST. The remaining studies used some of its components. Twenty-four studies were effective on changing parent behavior. Issues that still require more empirical investigation are discussed.

RESUMO Buscou-se responder quais procedimentos têm sido utilizados para treinar pais no âmbito da saúde mental, qual a frequência do uso do treinamento de habilidades comportamentais e seus componentes, e qual a efetividade de tais procedimentos. Foi conduzida uma revisão sistemática utilizando-se a base Education Collection ProQuest. Termos de busca foram "behavior skills training" (BST) e "parents" e seus correlatos em português. Artigos publicados entre 2010 e 2019 foram analisados, com ênfase nos procedimentos de treino de pais e seus efeitos. Dentre os 28 artigos analisados, 4 usaram o BST. Os outros estudos usaram algum de seus componentes. Vinte e quatro estudos foram efetivos para mudar o comportamento dos pais. Discutem-se questões que ainda necessitam mais investigação empírica.

Translation and Cultural Adaptation to European Portuguese of the "Measure of Moral Distress - Healthcare Professionals" Scale: A Cross-Sectional Multicenter Study.

INTRODUCTION: Moral distress occurs when one knows the morally correct action to take but is constrained from taking that action. The aims of this study were to translate into European Portuguese and culturally adapt the "Measure of Moral Distress - Healthcare Professionals" questionnaire to the context of the Portuguese healthcare system and to explore the frequency and intensity of moral distress occurring among medical students. MATERIAL AND METHODS: The "Measure of Moral Distress - Healthcare Professionals" questionnaire was translated and culturally adapted to European Portuguese, following the internationally accepted "COnsensus-based Standards for the selection of health Measurement INstruments". Afterwards, a web-based survey was conducted, following the "Checklist for Reporting Results of Internet E-Surveys" guidelines. Medical students were asked to rate potentially morally distressing situations on frequency and intensity. RESULTS: Of approximately 4300 medical students, 939 (22%) completed the survey. Participants experienced, on average, 16 morally distressing situations. Median of composite score of moral stress was 79 (IQR 44 - 118). Only 31% of the students felt well prepared to handle a morally distressing situation, 26% considered leaving medical school and 28% thought about choosing a non-clinical specialty due to moral distress. CONCLUSION: Despite a plethora of studies on this topic, the results suggested that moral distress is still a common phenomenon among medical students with a cumulative effect over time. These results emphasize the importance of a critical review of medical education, reducing the harmful effects of preventable psychological phenomena in clinical practice and in the lives of future healthcare professionals.

Introdução: O sofrimento moral ocorre quando um profissional de saúde sabe qual a ação moralmente correta a adotar, mas identifica um obstáculo que o constrange de realizar. Os objetivos deste estudo foram traduzir para Português Europeu e adaptar culturalmente para o contexto do sistema de saúde Português o questionário "Measure of Moral Distress ­ Healthcare Professionals" e explorar a frequência e intensidade deste fenómeno entre estudantes de medicina. Material e Métodos: Primeiro, traduzimos e adaptámos culturalmente para português Europeu o questionário "Measure of Moral Distress ­ Healthcare Professionals", seguindo o protocolo "COnsensus-based Standards for the selection of health Measurement INstruments". Depois, elaborámos um questionário seguindo as normas de orientação "Checklist for Reporting Results of Internet E-Surveys". Os estudantes de Medicina identificaram situações potencialmente causadoras de sofrimento moral em frequência e intensidade. Resultados: De aproximadamente 4300 participantes, 939 (22%) completaram o questionário. Os estudantes experienciaram, em média, 16 situações causadoras de sofrimento moral. A mediana da cotação composta de sofrimento moral foi 79 (IQR 44 - 118). Apenas 31% dos estudantes se sentem bem ou muito bem preparados para lidar com estas situações, 26% já consideraram deixar o curso de Medicina e 28% já pensaram escolher uma especialidade não clínica por este motivo. Conclusão: Apesar de vários estudos na área, os resultados sugerem que o sofrimento moral é um fenómeno comum entre alunos de medicina e a sua experiência mostra um efeito cumulativo ao longo do tempo. Estes resultados enfatizam a importância de rever criteriosamente o currículo de educação médica, de forma a reduzir os danos de um fenómeno evitável na prática clínica e nas vidas dos futuros profissionais de saúde.

Myosin VI regulates ciliogenesis by promoting the turnover of the centrosomal/satellite protein OFD1.

The actin motor protein myosin VI is a multivalent protein with diverse functions. Here, we identified and characterised a myosin VI ubiquitous interactor, the oral-facial-digital syndrome 1 (OFD1) protein, whose mutations cause malformations of the face, oral cavity, digits and polycystic kidney disease. We found that myosin VI regulates the localisation of OFD1 at the centrioles and, as a consequence, the recruitment of the distal appendage protein Cep164. Myosin VI depletion in non-tumoural cell lines causes an aberrant localisation of OFD1 along the centriolar walls, which is due to a reduction in the OFD1 mobile fraction. Finally, loss of myosin VI triggers a severe defect in ciliogenesis that could be, at least partially, ascribed to an impairment in the autophagic removal of OFD1 from satellites. Altogether, our results highlight an unprecedent layer of regulation of OFD1 and a pivotal role of myosin VI in coordinating the formation of the distal appendages and primary cilium with important implications for the genetic disorders known as ciliopathies.

The 3D architecture and molecular foundations of de novo centriole assembly via bicentrioles.

Centrioles are structurally conserved organelles, composing both centrosomes and cilia. In animal cycling cells, centrioles often form through a highly characterized process termed canonical duplication. However, a large diversity of eukaryotes assemble centrioles de novo through uncharacterized pathways. This unexplored diversity is key to understanding centriole assembly mechanisms and how they evolved to assist specific cellular functions. Here, we show that, during spermatogenesis of the bryophyte Physcomitrium patens, centrioles are born as a co-axially oriented centriole pair united by a cartwheel. Interestingly, we observe that these centrioles are twisted in opposite orientations. Microtubules emanate from the bicentrioles, which localize to the spindle poles during cell division. After their separation, the two resulting sister centrioles mature asymmetrically, elongating specific microtubule triplets and a naked cartwheel. Subsequently, two motile cilia are assembled that appear to alternate between different motility patterns. We further show that centriolar components SAS6, Bld10, and POC1, which are conserved across eukaryotes, are expressed during spermatogenesis and required for this de novo biogenesis pathway. Our work supports a scenario where centriole biogenesis, while driven by conserved molecular modules, is more diverse than previously thought.

Biophysical and Quantitative Principles of Centrosome Biogenesis and Structure.

The centrosome is a main orchestrator of the animal cellular microtubule cytoskeleton. Dissecting its structure and assembly mechanisms has been a goal of cell biologists for over a century. In the last two decades, a good understanding of the molecular constituents of centrosomes has been achieved. Moreover, recent breakthroughs in electron and light microscopy techniques have enabled the inspection of the centrosome and the mapping of its components with unprecedented detail. However, we now need a profound and dynamic understanding of how these constituents interact in space and time. Here, we review the latest findings on the structural and molecular architecture of the centrosome and how its biogenesis is regulated, highlighting how biophysical techniques and principles as well as quantitative modeling are changing our understanding of this enigmatic cellular organelle.

Patterns of selection against centrosome amplification in human cell lines.

The presence of extra centrioles, termed centrosome amplification, is a hallmark of cancer. The distribution of centriole numbers within a cancer cell population appears to be at an equilibrium maintained by centriole overproduction and selection, reminiscent of mutation-selection balance. It is unknown to date if the interaction between centriole overproduction and selection can quantitatively explain the intra- and inter-population heterogeneity in centriole numbers. Here, we define mutation-selection-like models and employ a model selection approach to infer patterns of centriole overproduction and selection in a diverse panel of human cell lines. Surprisingly, we infer strong and uniform selection against any number of extra centrioles in most cell lines. Finally we assess the accuracy and precision of our inference method and find that it increases non-linearly as a function of the number of sampled cells. We discuss the biological implications of our results and how our methodology can inform future experiments.

A first-takes-all model of centriole copy number control based on cartwheel elongation.

How cells control the numbers of subcellular components is a fundamental question in biology. Given that biosynthetic processes are fundamentally stochastic it is utterly puzzling that some structures display no copy number variation within a cell population. Centriole biogenesis, with each centriole being duplicated once and only once per cell cycle, stands out due to its remarkable fidelity. This is a highly controlled process, which depends on low-abundance rate-limiting factors. How can exactly one centriole copy be produced given the variation in the concentration of these key factors? Hitherto, tentative explanations of this control evoked lateral inhibition- or phase separation-like mechanisms emerging from the dynamics of these rate-limiting factors but how strict centriole number is regulated remains unsolved. Here, a novel solution to centriole copy number control is proposed based on the assembly of a centriolar scaffold, the cartwheel. We assume that cartwheel building blocks accumulate around the mother centriole at supercritical concentrations, sufficient to assemble one or more cartwheels. Our key postulate is that once the first cartwheel is formed it continues to elongate by stacking the intermediate building blocks that would otherwise form supernumerary cartwheels. Using stochastic models and simulations, we show that this mechanism may ensure formation of one and only one cartwheel robustly over a wide range of parameter values. By comparison to alternative models, we conclude that the distinctive signatures of this novel mechanism are an increasing assembly time with cartwheel numbers and the translation of stochasticity in building block concentrations into variation in cartwheel numbers or length.

Plk4 triggers autonomous de novo centriole biogenesis and maturation.

Centrioles form centrosomes and cilia. In most proliferating cells, centrioles assemble through canonical duplication, which is spatially, temporally, and numerically regulated by the cell cycle and the presence of mature centrioles. However, in certain cell types, centrioles assemble de novo, yet by poorly understood mechanisms. Herein, we established a controlled system to investigate de novo centriole biogenesis, using Drosophila melanogaster egg explants overexpressing Polo-like kinase 4 (Plk4), a trigger for centriole biogenesis. We show that at a high Plk4 concentration, centrioles form de novo, mature, and duplicate, independently of cell cycle progression and of the presence of other centrioles. Plk4 concentration determines the temporal onset of centriole assembly. Moreover, our results suggest that distinct biochemical kinetics regulate de novo and canonical biogenesis. Finally, we investigated which other factors modulate de novo centriole assembly and found that proteins of the pericentriolar material (PCM), and in particular γ-tubulin, promote biogenesis, likely by locally concentrating critical components.

Inequalities in Children's Experiences of Home Learning during the COVID-19 Lockdown in England.

This paper combines novel data on the time use, home-learning practices and economic circumstances of families with children during the COVID-19 lockdown with pre-lockdown data from the UK Time Use Survey to characterise the time use of children and how it changed during lockdown, and to gauge the extent to which changes in time use and learning practices during this period are likely to reinforce the already large gaps in educational attainment between children from poorer and better-off families. We find considerable heterogeneity in children's learning experiences - amount of time spent learning, activities undertaken during this time and availability of resources to support learning. Concerningly, but perhaps unsurprisingly, this heterogeneity is strongly associated with family income and in some instances more so than before lockdown. Furthermore, our analysis suggests that any impacts of inequalities in time spent learning between poorer and richer children are likely to be compounded by inequalities not only in learning resources available at home, but also in those provided by schools.